Mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction are critical to the pathophysiology of diabetes, obesity and insulin resistance as well to the vascular complications of these disorders. However, efforts to mitigate mitochondrial ROS production and oxidative damage have been limited by poor antioxidant entry into this compartment. Recently, mitochondrial targeted antioxidants have attracted attention as potential therapeutic agents. We recently carried out several studies of a mitochondrial targeted coenzyme Q analog termed mitoQ (mitoquinol, mitoquinone, or a combination of these redox cycling molecules). We demonstrated both prooxidant and antioxidant effects. We also reported the novel finding that mitoQ has important metabolic effects including increased respiration and induction of nutrient selectivity favoring glucose oxidation over fatty acid oxidation. In spite of prooxidant effects, several investigators have reported that mitochondrial targeted coenzyme Q analogs (MTQAs) offer effective therapy in animal models of disease states where pathology can be traced to oxidative damage. The dual antioxidant and prooxidant effects of MTQAs are discussed and further addressed as part of this application. The proposed research addresses several gaps in our knowledge of MTQAs. These involve interactions of MTQAs with the respiratory chain, the mechanism(s) underlying the metabolic effects of MTQAs, and the effectiveness of MTQAs in the setting of diabetes, obesity, and insulin resistance. Briefly stated, our objectives are: 1. Assess the metabolic effects of MTQAs in cultured cells and determine the mechanisms responsible. 2. Further delineate the prooxidant and antioxidant effects of MTQAs and obtain mechanistic information concerning mitochondrial sites where these effects arise. Determine the balance between prooxidant and antioxidant effects. Determine whether the redox effects contribute mechanistically to metabolic effects. 3. Determine whether MTQAs have protective effects in high-fat fed insulin resistant obese mice and in insulin deficient diabetic mice. 4. Determine the effects of MTQAs on mitochondrial membrane potential and respiratory coupling when administered to live mice and delineate the mechanism(s) underlying this effect. PUBLIC HEALTH RELEVANCE: Relevance to the VA: Obesity, insulin resistance, insulin deficient diabetes, and associated complications are highly prevalent among veterans. Mitochondrial reactive oxygen species are critical to the pathophysiology underlying these problems. This work may lead to new therapy for these problems by uncovering novel information about the mechanism(s) of action and effectiveness of mitochondrial targeted antioxidant compounds.